Clinical significance of increased expression of Nijmegen breakage syndrome gene (NBS1) in human primary liver cancer

Purpose: As a DNA repair-associated gene essential for maintaining genomic instability, Nijmegen breakage syndrome gene (NBS1), codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. The aim of this study is to investigate the molecular alteration of Nbs1 in human primary liver cancer, including HBV-associated hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods: The expression levels of Nbs1 in 110 cases of primary liver cancer, including 85 HCCs and 25 ICCs, were detected by immunohistochemistry, real-time RT-PCR and Western blot analysis. The percentage of Ki-67 antigen-positive cells and the level of phosphorylated histone H2AX (γ-H2AX) were detected to evaluate the relationship of Nbs1 expression with proliferation and the degree of DNA damage in HCC cells. Results: Increased Nbs1 expression was observed in tumor compared to corresponding adjacent non-tumor tissue in 54.6 and 47.3 % of HCC cases detected with frozen tissues and paraffin sections. Higher frequency of increased Nbs1 expression was shown in poorly differentiated HCCs (p = 0.0265) and in all poorly differentiated ICCs, indicating the increased Nbs1 expression is associated with the degree of malignancy of HCC cells. Moreover, the percentage of Ki-67-positive cells and the level of γ-H2AX correlate well with increased Nbs1 expression in HCC cases, suggesting an activated DNA damage response in proliferating HCC cells with increased Nbs1 expression. Conclusion: Increased Nbs1 expression might play a significant role in liver cancer progression, and the status of Nbs1 expression might be helpful for evaluation of the degree of malignancy of primary liver cancer.